WO2023088231A1 - Préparation nanocristalline d'inhibiteur de rock2 et son procédé de préparation - Google Patents

Préparation nanocristalline d'inhibiteur de rock2 et son procédé de préparation Download PDF

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WO2023088231A1
WO2023088231A1 PCT/CN2022/131872 CN2022131872W WO2023088231A1 WO 2023088231 A1 WO2023088231 A1 WO 2023088231A1 CN 2022131872 W CN2022131872 W CN 2022131872W WO 2023088231 A1 WO2023088231 A1 WO 2023088231A1
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nanocrystal
preparation
rock2 inhibitor
polysorbate
rock2
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PCT/CN2022/131872
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English (en)
Chinese (zh)
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卢迪
朱朝露
张志兵
牛生盼
卢永杰
徐佳佳
张莎莎
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北京泰德制药股份有限公司
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Priority to CA3238675A priority Critical patent/CA3238675A1/fr
Publication of WO2023088231A1 publication Critical patent/WO2023088231A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • the invention relates to the field of medicine, in particular, the invention relates to a nanocrystal preparation of a ROCK2 inhibitor and a preparation method thereof.
  • Idiopathic pulmonary fibrosis is a progressive respiratory disease characterized by pulmonary fibrosis and reduction and loss of lung function. The median survival period is 2.5-3 years.
  • IPF Idiopathic pulmonary fibrosis
  • ROCK2-targeted drugs the United States is conducting a phase 2 clinical study for IPF (Kadmon, USA), and preliminary results have confirmed the safety and effectiveness of ROCK2 inhibitors in the treatment of IPF.
  • [6-[4-[[4-(1H-pyrazol-4-yl)phenyl]amino]pyrimidin-2-yl]-1-methyl-1H-indol-2-yl](3,3 -Difluoroazetidin-1-yl)methanone is a new type of highly selective ROCK2 inhibitor with a new target and a new structure type completely independently developed by Beijing Tide Pharmaceutical Co., Ltd., from the perspective of patient compliance From this point of view, choose oral preparations for the treatment of IPF.
  • the high selectivity of its target greatly reduces the safety risk.
  • Our company has obtained the compound patent in the United States, and has applied for compound patents in China, the European Union, Japan, South Korea, India, Canada, Australia and other countries and regions.
  • [6-[4-[[4-(1H-pyrazol-4-yl)phenyl]amino]pyrimidin-2-yl]-1-methyl-1H-indol-2-yl](3,3 -Difluoroazetidin-1-yl)methanone is a light yellow to yellow solid powder with poor solubility and is insoluble in water and pH1.0 ⁇ pH6.8 cache salt solution. Poor physical properties, easy stickiness, static electricity, aggregation. Therefore, how to prepare the preparation of the compound and improve the dissolution rate of the product has become a technical problem to be solved urgently by those skilled in the art.
  • An object of the present invention is to provide a nanocrystal preparation of a ROCK2 inhibitor and a preparation method thereof, so as to improve the dissolution rate of the ROCK2 inhibitor.
  • the specific technical scheme is as follows:
  • the present invention firstly provides a nanocrystalline preparation comprising a ROCK2 inhibitor and a stabilizer, the ROCK2 inhibitor being a compound of formula (I),
  • Ring A is The above group is connected to the pyrimidine ring through one of the two positions marked with * or **, and the other position is connected to the carbonyl;
  • n is independently at each occurrence an integer of 0, 1, 2 or 3;
  • n each occurrence is independently an integer of 0, 1 or 2;
  • Ring A is The above group is connected to the pyrimidine ring through the position marked with *, and connected to the carbonyl group through the position marked with **, wherein R 10 is selected from H and C 1-6 alkyl, preferably H or methyl;
  • R is selected from H and C 1-6 alkyl
  • R 2 is selected from H and C 1-6 alkyl
  • R 3 , R 4 , R 7 and R 8 is independently selected from H, halogen, -NR 5 R 6 , -OH, C 1-6 alkyl and -OR 5 ;
  • alkylene, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are each optionally selected at each occurrence by one or more independently selected from halogen, C Substituents of -6 alkyl and -OR 5 ;
  • R 5 and R 6 are each independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl;
  • the present invention also provides a preparation method of the nanocrystal preparation, which comprises grinding the ROCK2 inhibitor and the stabilizer.
  • Another object of the present invention is the method and application of the nanocrystal preparation in the prevention, alleviation and/or treatment of idiopathic pulmonary fibrosis.
  • Fig. 1 and Fig. 2 are the stripping curves of comparative examples 1-3 of the present invention.
  • Fig. 3 is the stripping curve of embodiment 8-9 of the present invention and comparative example
  • Fig. 4 ⁇ Fig. 6 are respectively the stripping curve of embodiment 8 nano-suspension of the present invention, embodiment 10-15 nano-tablet formulation and comparative example;
  • Fig. 7 is the dissolution curve of the nanosuspension of Example 8, the nanochip tablet of Example 15, the nanocrystalline capsules of Examples 24-25 and the comparative example of the present invention.
  • nanocrystal refers to nanocrystals, and also to nanosuspension, which means a stable colloidal dispersion system formed by dispersing nanoscale drug particles in water in the presence of a stabilizer.
  • alkylene means a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, Propylene or Butylene.
  • alkyl is defined as a linear or branched saturated aliphatic hydrocarbon.
  • the alkyl group has 1 to 12, eg, 1 to 6 carbon atoms.
  • C 1-6 alkyl refers to a linear or branched group of 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl radical, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or n-hexyl) optionally replaced by 1 or more (such as 1 to 3) suitable substituents
  • halogen substitution in which case the group is called "haloalkyl”
  • haloalkyl for example CH 2 F, CHF 2 , CF 3 , CCl 3 , C 2 F 5 , C 2 Cl 5 , CH 2
  • C 1-4 alkyl refers to a linear or branched aliphatic hydrocarbon chain of 1 to 4 carbon atoms (i.e. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl).
  • alkenyl means a linear or branched monovalent hydrocarbon group containing one double bond and having 2-6 carbon atoms (“ C2-6 alkenyl”).
  • the alkenyl is, for example, vinyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-butenyl, -hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl and 4-methyl-3-pentenyl.
  • the compound of the present invention contains an alkenylene group, the compound may exist in pure E (ent ought) form, pure Z (zusammen) form, or any mixture thereof.
  • alkynyl denotes a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, eg ethynyl or propynyl.
  • cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , cyclooctyl, cyclononyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.)), which are optionally substituted with 1 or more (such as 1 to 3) suitable substituents.
  • monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl , cyclooctyl,
  • the cycloalkyl has 3 to 15 carbon atoms.
  • C 3-6 cycloalkyl refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclopropyl) of 3 to 6 ring-forming carbon atoms. hexyl) optionally substituted by 1 or more (such as 1 to 3) suitable substituents, eg methyl substituted cyclopropyl.
  • cycloalkylene means ring carbons having, for example, 3-10 (suitably 3-8, more suitably 3-6) ring carbons Atoms of saturated (i.e., “cycloalkylene” and “cycloalkyl”) or unsaturated (i.e., having one or more double and/or triple bonds within the ring) monocyclic or polycyclic hydrocarbon rings, which Including but not limited to (ylidene)cyclopropyl (ring), (ylidene)cyclobutyl (ring), ((ylidene)cyclopentyl (ring), ((ylidene)cyclohexyl (ring), (ylidene)cycloheptyl ( (ring), (sub)cyclooctyl (ring), (sub)cyclononyl (ring), (sub)cyclohexenyl (ring), etc.
  • heterocyclyl As used herein, the terms “heterocyclyl”, “heterocyclylene” and “heterocycle” mean having, for example, 3-10 (suitably having 3-8, more suitably having 3-6) ring atoms, wherein at least one ring atom is a heteroatom selected from N, O, and S and the remaining ring atoms are C saturated (i.e., heterocycloalkyl) or partially unsaturated (i.e., with one or more double bond and/or triple bond) cyclic group.
  • a "3-10 membered (sub)heterocyclic (group)” has 2-9 (such as 2, 3, 4, 5, 6, 7, 8 or 9) ring carbon atoms and is independently selected from N A saturated or partially unsaturated (sub)heterocyclic ring (group) of one or more (for example, 1, 2, 3 or 4) heteroatoms of , O and S.
  • heterocyclylene and heterocycle include, but are not limited to: ()oxiranyl, () aziridinyl, (azetidinyl), ()oxy Heterocyclobutyl (oxetanyl), (sub)tetrahydrofuranyl, (sub)dioxolinyl (dioxolinyl), (sub)pyrrolidinyl, (sub)pyrrolidinyl, (sub)imidazolidinyl, (sub) ) pyrazolidinyl, (sub)pyrrolinyl, (sub)tetrahydropyranyl, (sub)piperidinyl, (sub)morpholinyl, (sub)dithianyl (dithianyl), (sub) Thiomorpholinyl, piperazinyl or trithianyl.
  • the groups also encompass bicyclic systems, including spiro, fused or bridged systems (such as 8-azaspiro[4.5]decane, 3,9-diazaspiro[5.5]undecane, 2-azaspiro[5.5]undecane, Heterobicyclo[2.2.2]octane, etc.).
  • Heterocyclylene and heterocycle(yl) groups may be optionally substituted with one or more (eg 1, 2, 3 or 4) suitable substituents.
  • the terms "()arylene” and "aromatic ring” refer to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated ⁇ -electron system.
  • C 6-10 ()arylene” and “C 6-10 aromatic ring” mean an aromatic group containing 6 to 10 carbon atoms, such as ()phenylene (benzene ring) or (ylidene) naphthyl (naphthalene ring).
  • ()Arylene and aromatic rings are optionally substituted with 1 or more (such as 1 to 3) suitable substituents (eg halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.) .
  • heteroarylene and “heteroaromatic ring” refer to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contain at least one heteroatom which may be the same or different (the heteroatoms are for example oxygen, nitrogen or sulfur), and, additionally, in each case may be benzo-fused.
  • “(y)heteroaryl” or “heteroaromatic ring” is selected from (y)thienyl, (y)furyl, (y)pyrrolyl, (y)oxazolyl, ()thiazolyl, (Yellow) imidazolyl, (lower) pyrazolyl, (lower) isoxazolyl, (lower) isothiazolyl, (lower) oxadiazolyl, (lower) triazolyl, (lower) thiadiazolyl etc., and their benzo derivatives; or (sub)pyridyl, (sub)pyridazinyl, (sub)pyrimidinyl, (sub)pyrazinyl, (sub)triazinyl, etc. derivative.
  • aralkyl preferably denotes an aryl or heteroaryl substituted alkyl group, wherein aryl, heteroaryl and alkyl are as defined herein.
  • the aryl group can have 6-14 carbon atoms
  • the heteroaryl group can have 5-14 ring atoms
  • the alkyl group can have 1-6 carbon atoms.
  • Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • halo or halogen group is defined to include F, Cl, Br or I.
  • substituted means that one or more (e.g., one, two, three or four) hydrogens on the designated atom are replaced by a selection from the indicated group, provided that no more than the designated atom is present.
  • the normal valences of the cases and such substitutions result in stable compounds. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together Selected optional substituents are substituted. If the nitrogen of a substituent is described as being optionally substituted with one or more of the list of substituents, one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected Substituent substitution.
  • each substituent is selected independently of the other. Accordingly, each substituent may be the same as or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10, under reasonable conditions.
  • the point of attachment of a substituent may be from any suitable position of the substituent.
  • the present invention also includes all pharmaceutically acceptable isotopically labeled compounds which are identical to the compounds of the present invention except that one or more atoms have been labeled with the same atomic number but an atomic mass or mass number different from the atomic mass prevailing in nature. or mass number of atomic substitutions.
  • isotopes suitable for inclusion in compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., deuterium ( 2H ), tritium ( 3H )); isotopes of carbon (e.g. , 11C , 13C , and 14C ).
  • isotopes of chlorine such as 36 Cl
  • isotopes of fluorine such as 18 F
  • isotopes of iodine such as 123 I and 125 I
  • isotopes of nitrogen such as 13 N and 15 N); , 17 O and 18 O
  • phosphorus isotopes eg 32 P
  • sulfur isotopes eg 35 S.
  • Certain isotopically-labeled compounds of the invention eg, those incorporating radioactive isotopes
  • are useful in drug and/or substrate tissue distribution studies eg, assays).
  • the radioisotopes tritium ( ie3H ) and carbon-14 ( ie14C ) are particularly useful for this purpose because of their ease of incorporation and ease of detection.
  • Substitution with positron-emitting isotopes such as 11 C, 18 F, 15 O, and 13 N can be used in positron emission tomography (PET) studies to examine substrate receptor occupancy.
  • Isotopically labeled compounds of the invention can be prepared by methods analogous to those described in the accompanying Schemes and/or Examples and Preparations by using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.
  • Pharmaceutically acceptable solvates of the invention include those wherein the solvent of crystallization may be isotopically substituted, eg, D2O , acetone- d6 or DMSO- d6 .
  • stereoisomer means isomers formed as a result of at least one asymmetric center.
  • compounds with one or more (e.g., one, two, three or four) asymmetric centers which can give rise to racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereoisomers.
  • Certain individual molecules may also exist as geometric isomers (cis/trans).
  • compounds of the present invention may exist as mixtures of two or more structurally distinct forms (commonly referred to as tautomers) in rapid equilibrium.
  • tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers wait. It is to be understood that the scope of this application encompasses all such ratios in any proportion (e.g., 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%) %) isomers or mixtures thereof.
  • Solid lines can be used in this article solid wedge or imaginary wedge Depicts the chemical bonds of the compounds of the invention.
  • the use of a solid line to delineate a bond to an asymmetric carbon atom is intended to indicate that all possible stereoisomers at that carbon atom are included (eg, specific enantiomers, racemic mixtures, etc.).
  • the use of solid or dashed wedges to delineate bonds to asymmetric carbon atoms is intended to indicate that the stereoisomers shown exist.
  • solid and imaginary wedges are used to define relative rather than absolute stereochemistry.
  • the compounds of the present invention are intended to be stereoisomers (which include cis and trans isomers, optical isomers (such as R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformational isomers, atropisomers and mixtures thereof).
  • the compounds of the invention may exhibit more than one type of isomerism and consist of mixtures thereof, such as racemic mixtures and pairs of diastereoisomers.
  • the present invention covers all possible crystalline forms or polymorphs of the compounds of the present invention, which may be a single polymorph or a mixture of more than one polymorph in any proportion.
  • compositions of the invention may exist in free form for use in therapy, or, where appropriate, as pharmaceutically acceptable derivatives thereof.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, N-oxides, metabolites or prodrugs, which are administered to patients in need thereof Following administration, the compound of the invention or its metabolites or residues can be provided directly or indirectly. Therefore, when a "compound of the present invention" is referred to herein, it is also intended to cover the above-mentioned various derivative forms of the compound.
  • the pharmaceutically acceptable salts of the compounds of the present invention include acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate , citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate Salt, seabenzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleic acid Salt, malonate, methanesulfonate, methylsulfate, naphthylate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitic acid Salt, Pam
  • Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, benzathine penicillin salts, calcium salts, choline salts, diethylamine salts, diethanolamine salts, glycinate salts, lysine salts, magnesium salts, meglumine salts, ethanolamine salts, Potassium, sodium, tromethamine and zinc salts.
  • esters means an ester derived from each of the compounds of the general formula in this application, including physiologically hydrolyzable esters (hydrolyzable under physiological conditions to release the free acid or alcohol form of the present invention) compound).
  • the compounds of the invention may also themselves be esters.
  • the compounds of the invention may exist in the form of solvates, preferably hydrates, wherein the compounds of the invention comprise a polar solvent, such as water, methanol or ethanol in particular, as a structural element of the crystal lattice of the compound.
  • a polar solvent such as water, methanol or ethanol in particular, as a structural element of the crystal lattice of the compound.
  • the amount of polar solvent, especially water, may be present in stoichiometric or non-stoichiometric ratios.
  • nitrogen-containing heterocycles are capable of forming N-oxides since nitrogen requires available lone pairs of electrons to oxidize to oxides; nitrogen-containing heterocycle.
  • tertiary amines are capable of forming N-oxides.
  • N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include the use of peroxyacids such as peracetic acid and m-chloroperbenzoic acid (MCPBA), hydrogen peroxide, alkyl Hydrogen peroxides such as t-butyl hydroperoxide, sodium perborate and dioxiranes such as dimethyldioxirane are used to oxidize heterocycles and tertiary amines.
  • MCPBA m-chloroperbenzoic acid
  • hydrogen peroxide alkyl Hydrogen peroxides such as t-butyl hydroperoxide
  • sodium perborate and dioxiranes such as dimethyldioxirane
  • metabolites of the compounds of the present invention ie substances formed in vivo upon administration of the compounds of the present invention. Such products may result, for example, from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, enzymatic hydrolysis, etc., of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds produced by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolite thereof.
  • the present invention further includes within its scope prodrugs of the compounds of the invention, which are certain derivatives of the compounds of the invention which themselves may have little or no pharmacological activity when administered into or on the body. can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage. Typically such prodrugs will be functional group derivatives of the compound which are readily converted in vivo into the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Volume 14, ACS Symposium Series (T. Higuchi and V. Stella).
  • prodrugs of the present invention can be obtained, for example, by using certain moieties known to those skilled in the art as "pro-moiety (such as described in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985))". Prepared by substituting appropriate functional groups present in the compounds of the invention.
  • the invention also encompasses compounds of the invention which contain protecting groups.
  • protecting groups such as those described in T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which references are incorporated herein by reference.
  • Protecting groups may be removed at an appropriate subsequent stage using methods known in the art.
  • the term "effective amount” refers to the amount sufficient to achieve the desired therapeutic effect under the administration conditions, which leads to the improvement of pathological symptoms, disease progression, physiological conditions related thereto or induces resistance to the aforementioned diseases.
  • treating means reversing, alleviating, inhibiting the disorder or condition to which such term applies or the progression of one or more symptoms of such disorder or condition, or Such a disorder or condition or one or more symptoms of such a disorder or condition is prevented.
  • “Individual” as used herein includes a human or non-human animal.
  • Exemplary human subjects include human subjects suffering from a disease (eg, a disease described herein) (referred to as a patient) or normal subjects.
  • Non-human animals in the present invention include all vertebrates, such as non-mammals (e.g., birds, amphibians, reptiles) and mammals, such as non-human primates, livestock and/or domesticated animals (e.g., sheep, dogs, , cats, cows, pigs, etc.).
  • the present invention relates to a nanocrystalline formulation comprising a ROCK2 inhibitor and a stabilizer.
  • the present invention relates to a nanocrystalline preparation, wherein the ROCK2 inhibitor is a compound of formula (I),
  • Ring A is The above group is connected to the pyrimidine ring through one of the two positions marked with * or **, and the other position is connected to the carbonyl;
  • n is independently at each occurrence an integer of 0, 1, 2 or 3;
  • n each occurrence is independently an integer of 0, 1 or 2;
  • Ring A is The above group is connected to the pyrimidine ring through the position marked with *, and connected to the carbonyl group through the position marked with **, wherein R 10 is selected from H and C 1-6 alkyl, preferably H or methyl;
  • R is selected from H and C 1-6 alkyl
  • R 2 is selected from H and C 1-6 alkyl
  • R 3 , R 4 , R 7 and R 8 is independently selected from H, halogen, -NR 5 R 6 , -OH, C 1-6 alkyl and -OR 5 ;
  • alkylene, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, heteroaryl and aralkyl are each optionally selected at each occurrence by one or more independently selected from halogen, C Substituents of -6 alkyl and -OR 5 ;
  • R 5 and R 6 are each independently selected from H, C 1-6 alkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-14 membered Heteroaryl and C 6-12 aralkyl;
  • the present invention relates to a nanocrystalline preparation
  • the ROCK2 inhibitor is a compound of formula (II) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate thereof substances, N-oxides, isotope labels, metabolites or prodrugs,
  • each group is as defined above.
  • the present invention relates to a nanocrystalline preparation
  • the ROCK2 inhibitor is a compound of formula (III) or a pharmaceutically acceptable salt, ester, stereoisomer, polymorph, solvate thereof substances, N-oxides, isotope labels, metabolites or prodrugs,
  • R 10 is H or methyl, preferably methyl.
  • the present invention relates to a nanocrystalline preparation
  • the ROCK2 inhibitor is a compound of formula (IV), or a pharmaceutically acceptable salt (especially hydrochloride), ester, stereoisomer thereof , polymorphs, solvates, N-oxides, isotope labels, metabolites or prodrugs,
  • the chemical name of the compound of formula (IV) is: [6-[4-[[4-(1H-pyrazol-4-yl)phenyl]amino]pyrimidin-2-yl]-1-methyl-1H-ind Indol-2-yl](3,3-difluoroazetidin-1-yl)methanone.
  • the compound of formula (IV) can be prepared by a known method as a bulk drug, and can also be obtained through commercial channels, no matter which method is used, it is easy for those skilled in the art to realize, Therefore, the present invention will not be described in detail here.
  • nano-micronization can significantly increase the specific surface area of drug particles, which also increases the free energy of the entire preparation preparation system, resulting in system instability;
  • the action temperature caused by the mechanical energy during the grinding process, the newly formed nanoparticles will re-agglomerate and recrystallize under the influence of the free energy change.
  • the stabilizer is adsorbed on the surface of the drug particles to block the re-aggregation of the drug particles, thereby increasing the effective surface area and significantly improving the stability of the nanosuspension.
  • the stabilizer in addition to improving the wettability of the drug and stabilizing the particle size of the drug, can also improve the dissolution rate by improving the particle size stability of the ROCK2 inhibitor nanocrystal after solidification, drying and reconstitution.
  • a person skilled in the art can select a suitable stabilizer according to the description of the function of the stabilizer herein in the present invention.
  • polysorbate 20 Including but not limited to polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 65, polysorbate 80, polysorbate 85, povidone K29/32, polyoxyethylene fatty acid ester, polo Sharm 188, Poloxamer 407, Hydroxypropylcellulose (HPC), Hydroxypropylmethylcellulose (HPMC 3cps), Polyvinylpyrrolidone (PVP K30), Poloxamer (Pluronic F68 and Pluronic F127) , sodium dodecyl sulfate (SDS), docusate sodium (DSS), polyethylene glycol 15-hydroxystearate, polyoxyethylene castor oil, copovidone, etc.
  • HPC Hydroxypropylcellulose
  • HPMC 3cps Hydroxypropylmethylcellulose
  • PVP K30 Polyvinylpyrrolidone
  • Poloxamer Poloxamer (Pluronic F68 and Pluronic F127) , sodium dodecyl s
  • the present invention relates to a nanocrystalline preparation, wherein the stabilizer is selected from polysorbate, povidone, hydroxypropyl methylcellulose, polyethylene glycol, polyvinyl alcohol, polyoxyethylene castor One or more of sesame oil, poloxamer, sodium lauryl sulfate, lactose, and mannitol.
  • the stabilizer is selected from polysorbate, povidone, hydroxypropyl methylcellulose, polyethylene glycol, polyvinyl alcohol, polyoxyethylene castor One or more of sesame oil, poloxamer, sodium lauryl sulfate, lactose, and mannitol.
  • the present invention relates to a nanocrystal preparation
  • the particle size D90 of the nanocrystal preparation is 50-1500nm, preferably 50-1000nm, preferably 50-500nm, preferably 80-300nm, more preferably 50nm, 100nm, 150nm, 200nm, 250nm, 300nm, 400nm, 500nm, 600nm, 700nm, 800nm, 900nm or 1000nm.
  • the present invention relates to a nanocrystalline preparation, and the particle size range of the ROCK2 inhibitor is preferably D 90 5-300 ⁇ m, preferably 10-100 ⁇ m, more preferably 10-50 ⁇ m.
  • the present invention relates to a nanocrystal preparation, based on the total weight of the nanocrystal preparation, the weight percentage of the ROCK2 inhibitor can be 1%-55%, 4%-50%, 1%- 10%, 10%-40%, 10%-35%, 20%-30% or 30%-40%, can also be 1%, 2%, 3%, 4%, 4.5%, 5%, 6% , 7%, 8%, 9%, 9.5%, 10%, 11%, 12%, 13%, 14%, 15%, 15%, 16%, 18%, 19%, 20%, 21%, 22 %, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39% or 40%.
  • the present invention relates to a nanocrystal preparation, based on the total weight of the nanocrystal preparation, the weight percentage of the stabilizer can be 0.1%-55%, 0.1%-30%, 0.5%-1 %, 1%-10%, 10%-20% or 20%-30%, can also be 1%, 2%, 2.5%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 9.5%, 10%, 11%, 12%, 13%, 14%, 15%, 15%, 16%, 18%, 19%, 20%, 21%, 22%, 23%, 24% , 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, or 40%.
  • the present invention relates to a nanocrystalline formulation, wherein the weight ratio of ROCK2 inhibitor and stabilizer can be 1:10 to 10:1, 1:9 to 9:1, 1:8 to 8: 1. 1:7 to 7:1, 1:6 to 6:1, 1:5 to 5:1, 1:4 to 4:1, 1:3 to 3:1, 1:2 to 2:1, 1:1; can also be 4:1 to 1:1 or 1:1 to 1:2; can also be 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1, 1:2, 1:3, 5:4, 5:3, or 5:2.
  • the weight ratio of ROCK2 inhibitor and stabilizer can be 1:10 to 10:1, 1:9 to 9:1, 1:8 to 8: 1. 1:7 to 7:1, 1:6 to 6:1, 1:5 to 5:1, 1:4 to 4:1, 1:3 to 3:1, 1:2 to 2:1, 1:1; can also be 4:1 to 1:1 or 1:1 to 1:2; can also be 10:1, 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1, 2:1, 1:1
  • the present invention relates to a nanocrystal formulation further comprising excipients.
  • the present invention relates to a nanocrystalline formulation, wherein said excipient is selected from the group consisting of fillers; wetting agents; sweeteners or flavoring agents; surfactants; Glidants or anti-adherents; release modifiers; coating agents; emulsifiers; solubilizers;
  • the present invention relates to a nanocrystalline preparation, wherein the excipient comprises a filler; the filler can improve the material properties of the active ingredient, improve stickiness and electrostatic properties, thereby facilitating the subsequent shaping of the composition, such as pressing Tablets, filled capsules, etc., play an important role in the preparation of solid preparations.
  • Fillers can also adjust the dissolution rate of the formulation.
  • fillers commonly used in the technical field can be selected, including but not limited to microcrystalline cellulose, mannitol, lactose, starch, pregelatinized starch, dextrin, calcium phosphate dihydrate, anhydrous phosphoric acid One or at least two kinds of calcium hydrogen.
  • the weight percentage of the filler can be 1%-80%; more specifically, in some embodiments, the weight percentage of the filler can be 20%-70%, 30%-60% or 50-70%, etc., such as 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65% or 70% etc.
  • the filler is selected from one or more of microcrystalline cellulose, lactose, and mannitol. Preferably, the filler is mannitol.
  • the present invention is directed to a nanocrystalline formulation wherein the excipients comprise lubricants which facilitate various processing steps including mixing of components, tabletting; for example lubricants allow pressure distribution during tabletting Uniformity, and make the density of the tablet uniform; the force required to push the tablet out of the die hole is reduced.
  • lubricants allow pressure distribution during tabletting Uniformity, and make the density of the tablet uniform; the force required to push the tablet out of the die hole is reduced.
  • Another possible function of the lubricant is to improve the appearance of the tablet, making the surface of the tablet bright and smooth.
  • lubricants commonly used in the technical field can be selected, including but not limited to magnesium stearate, talcum powder, micropowder silica gel, sodium stearyl fumarate, glyceryl behenate and polyethylene glycol One or a combination of at least two, more preferably magnesium stearate.
  • the weight percentage of the lubricant can be 0.1% to 5%, 0.1%-1.5% or 0.5%-1%, etc., such as 0.1 %, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%, 1.4% or 1.5%, etc.
  • Described lubricant is selected from magnesium stearate, talcum powder, micropowder silica gel, sodium stearyl fumarate, glyceryl behenate and polyethylene glycol.
  • the present invention relates to a nanocrystalline formulation, wherein the excipient comprises a disintegrant.
  • disintegrants commonly used in the technical field can be selected, including but not limited to one or more of croscarmellose sodium and crospovidone.
  • the weight percentage of the disintegrant can be 0 to 20%, preferably 0 to 10%, more preferably 2 to 10%, For example 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%.
  • the present invention relates to a nanocrystalline formulation, wherein the excipient comprises a glidant.
  • commonly used glidants in the technical field can be selected, including but not limited to silicon dioxide and the like.
  • the weight percentage of the glidant may be 0 to 20%, preferably 0 to 15%, more preferably 2 to 12%, For example 2%, 2.5%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10% or 11%.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal preparation further contains a solvent.
  • solvents commonly used in the technical field can be selected, including but not limited to water, etc., preferably pure water.
  • the weight percentage of the solvent may be 0 to 99%, preferably 80 to 99%, more preferably 85% to 95%, for example 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, or 95%.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal preparation further contains a bacteriostatic agent.
  • bacteriostatic agents commonly used in the technical field can be selected, including but not limited to one or more of methylparaben and propylparaben.
  • the weight percentage of the bacteriostat can be 0 to 5%, preferably 0 to 1%, more preferably 0.01% to 0.5% , such as 0.1%, 0.2%, 0.3%, 0.4% or 0.5%.
  • the present invention relates to a nanocrystalline formulation, wherein the nanocrystalline formulation is selected from suspensions, tablets, capsules, granules, powders, lozenges and pills; preferably suspensions, tablets doses or capsules.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal preparation is a suspension comprising:
  • ROCK2 inhibitor preferably 1%, 2%, 3%, 4%, 4.5%, 5%, 6%, 7%, 8%, 9% or 10% ROCK2 inhibitor, more preferably 4%, 4.5%, 5% ROCK2 inhibitors;
  • - 1-10% stabilizer preferably 1%, 1.5%, 2%, 2.5%, 5%, 9%, 9.5% or 10% stabilizer.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a suspension comprising 11.13g of ROCK2 inhibitor, 0.77g of polysorbate 80, 5.00g of povidone K29/32 and 233.10 g purified water, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a suspension comprising 11.13g of ROCK2 inhibitor, 0.77g of polysorbate 80, 2.50g of povidone K29/32 and 235.60 g purified water, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a suspension comprising 11.13g of ROCK2 inhibitor, 0.77g of polysorbate 80, 2.50g of hypromellose and 235.60g of Purified water, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a suspension comprising 11.13g of ROCK2 inhibitor, 0.77g of polysorbate 80, 5.00g of hypromellose and 233.10g of Purified water, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a suspension comprising 250.08g ROCK2 inhibitor, 17.40g polysorbate 80, 111.60g povidone K29/32, 10.00g g methylparaben, 1.10g propylparaben and 5189.82g purified water, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a suspension comprising 55.19g ROCK2 inhibitor, 18.61g polysorbate 80, 99.25g polyoxyethylene castor oil, 2.23g Methylparaben, 0.25g propylparaben and 1065.09g purified water, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, most preferably 50-150nm .
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal preparation is a tablet, comprising:
  • ROCK2 inhibitor preferably 20-30% ROCK2 inhibitor, preferably 20%, 22%, 25%, 28% or 30% ROCK2 inhibitor;
  • - 1-20% stabilizer preferably 5-20% stabilizer, more preferably 5%, 8%, 10%, 13%, 15%, 18% or 20% stabilizer.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a tablet comprising 11.70g ROCK2 inhibitor, 3.15g polysorbate 80, 5.26g lactose, 1.05g polyethylene glycol 6000 , 16.03g mannitol, 4.94g silicon dioxide, 2.47g sodium lauryl sulfate, 2.96g microcrystalline cellulose, 2.96g croscarmellose sodium and 0.32g magnesium stearate, preferably, the The particle size of the ROCK2 inhibitor is 50-1000 nm, preferably 50-500 nm, more preferably 50-300 nm, most preferably 50-150 nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a tablet comprising 32.71g ROCK2 inhibitor, 14.81g polysorbate 80, 14.71g lactose, 2.94g polyethylene glycol 6000 , 43.63g mannitol, 16.00g silicon dioxide, 8.00g sodium lauryl sulfate, 12.80g microcrystalline cellulose, 12.80g croscarmellose sodium and 1.60g sodium stearyl fumarate, preferably , the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, most preferably 50-150nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a tablet comprising 3.34g ROCK2 inhibitor, 0.89g polysorbate 80, 1.80g lactose, 0.30g polyethylene glycol 6000 , 0.75g silicon dioxide, 0.75g sodium lauryl sulfate, 5.82g microcrystalline cellulose, 1.20g croscarmellose sodium and 0.15g sodium stearyl fumarate, preferably, the ROCK2 inhibitor
  • the particle size of the agent is 50-1000 nm, preferably 50-500 nm, more preferably 50-300 nm, most preferably 50-150 nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a tablet comprising 3.34g ROCK2 inhibitor, 0.89g polysorbate 80, 1.80g lactose, 0.30g polyethylene glycol 6000 , 0.75g silicon dioxide, 0.45g sodium lauryl sulfate, 4.50g microcrystalline cellulose, 1.62g pregelatinized starch, 1.20g croscarmellose sodium and 0.15g sodium stearyl fumarate,
  • the particle size of the ROCK2 inhibitor is 50-1000 nm, preferably 50-500 nm, more preferably 50-300 nm, most preferably 50-150 nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a tablet comprising 11.14g ROCK2 inhibitor, 2.97g polysorbate 80, 6.01g lactose, 1.00g polyethylene glycol 6000 , 1.00g silicon dioxide, 27.38g spray-dried mannitol and 0.50g sodium stearyl fumarate, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, Most preferably 50-150nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a tablet comprising 111.20g of ROCK2 inhibitor, 30.04g of polysorbate 80, 59.99g of lactose, 10.00g of polyethylene glycol 6000 , 10.00g silicon dioxide, 273.78g spray-dried mannitol and 5.00g sodium stearyl fumarate, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, Most preferably 50-150nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal preparation is a tablet, comprising:
  • ROCK2 inhibitor preferably 20-30% ROCK2 inhibitor, more preferably 20%, 22%, 25%, 28% or 30% ROCK2 inhibitor;
  • - 10-30% stabilizer preferably 20-30% stabilizer, more preferably 20%, 22%, 25%, 28% or 30% stabilizer.
  • the present invention relates to a nanocrystal formulation, wherein the nanocrystal is a tablet comprising 22.22g ROCK2 inhibitor, 20.00g polysorbate 80, 54.80g mannitol, 2.00g silicon dioxide and 1.00 g of sodium stearyl fumarate, preferably, the particle size of the ROCK2 inhibitor is 50-1000 nm, preferably 50-500 nm, more preferably 50-300 nm, most preferably 50-150 nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a tablet comprising 22.20g ROCK2 inhibitor, 10.00g polysorbate 80, 20.00g povidone K29/32, 44.80g Mannitol, 2.00g silicon dioxide and 1.00g sodium stearyl fumarate, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, most preferably 50- 150nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a tablet comprising 22.20g ROCK2 inhibitor, 10.00g polysorbate 80, 20.00g polyethylene glycol 6000, 44.80g manna Alcohol, 2.00g silicon dioxide and 1.00g sodium stearyl fumarate, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, most preferably 50-150nm .
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a tablet, comprising 22.20g ROCK2 inhibitor, 10.00g polysorbate 80, 20.00g poloxamer 188, 44.80g manna Alcohol, 2.00g silicon dioxide and 1.00g sodium stearyl fumarate, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, most preferably 50-150nm .
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a tablet comprising 22.20g ROCK2 inhibitor, 10.00g polysorbate 80, 20.00g polyvinyl alcohol, 44.80g mannitol, 2.00g silicon dioxide and 1.00g sodium stearyl fumarate, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, most preferably 50-150nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a tablet comprising 22.20g ROCK2 inhibitor, 10.00g polysorbate 80, 16.00g povidone K29/32, 4.00g Poloxamer 188, 44.80g mannitol, 2.00g silicon dioxide and 1.00g sodium stearyl fumarate, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, most preferably 50-150nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a tablet, comprising 22.20g ROCK2 inhibitor, 10.00g polysorbate 80, 4.00g povidone K29/32, 16.00g Poloxamer 188, 44.80g mannitol, 2.00g silicon dioxide and 1.00g sodium stearyl fumarate, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, most preferably 50-150nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a tablet, comprising 22.20g ROCK2 inhibitor, 10.00g polysorbate 80, 10.00g povidone K29/32, 10.00g Poloxamer 188, 44.80g mannitol, 2.00g silicon dioxide and 1.00g sodium stearyl fumarate, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, most preferably 50-150nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal preparation is a capsule, comprising:
  • ROCK2 inhibitor preferably 20-40% ROCK2 inhibitor, more preferably 20%, 25%, 30%, 35% or 40% ROCK2 inhibitor;
  • stabilizer preferably 20-30% stabilizer, more preferably 20%, 22%, 25%, 28% or 30% stabilizer.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a capsule, comprising 22.20g ROCK2 inhibitor, 6.00g polysorbate 80, 8.00g povidone K29/32, 4.00g Poloxamer and 20.00g of mannitol, preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, most preferably 50-150nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal is a capsule comprising 4.45g ROCK2 inhibitor, 1.20g polysorbate 80, 1.20g povidone K32/29, 0.80g Poloxamer 188 and 6.80 g of mannitol.
  • the particle size of the ROCK2 inhibitor is 50-1000 nm, preferably 50-500 nm, more preferably 50-300 nm, most preferably 50-150 nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal preparation is a nanocrystal enteric preparation selected from enteric-coated tablets or enteric-coated capsules.
  • the present invention relates to a nanocrystalline preparation, wherein the nanocrystalline preparation is a nanocrystalline enteric coated tablet, wherein the enteric coating material is selected from the group consisting of shellac, polyvinyl alcohol benzene diacetate Formate ester (PVAP), methacrylic acid copolymer, cellulose and its derivatives (cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl cellulose phthalate ( One or more of HPMCP)), acrylic resins (EuS100, EuL100).
  • the enteric coating material is selected from the group consisting of shellac, polyvinyl alcohol benzene diacetate Formate ester (PVAP), methacrylic acid copolymer, cellulose and its derivatives (cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropyl cellulose phthalate ( One or more of HPMCP)), acrylic resins (EuS100, EuL100).
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal preparation is a nanocrystal enteric-coated capsule, wherein the enteric-coated capsule is selected from gelatin enteric-coated capsules or hypromellose enteric-coated capsules,
  • the composition of the capsule material is selected from shellac, polyvinyl alcohol acetate phthalate (PVAP), methacrylic acid copolymer, cellulose and its derivatives (cellulose acetate phthalate (CAP), cellulose acetate trimellitate One or more of esters (CAT), hydroxypropyl cellulose phthalate (HPMCP)), acrylic resins (EuS100, EuL100).
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal preparation is a nanocrystal enteric-coated tablet, comprising:
  • ROCK2 inhibitor preferably 5-15% ROCK2 inhibitor, more preferably 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15% ROCK2 inhibitor;
  • - 1-90% stabilizer preferably 10-40% stabilizer, more preferably 15-25% stabilizer, for example, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22% %, 23%, 24% or 25% stabilizer.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal preparation is a nanocrystal enteric-coated tablet, comprising 5.56g ROCK2 inhibitor, 1.50g polysorbate 80, 1.00g porol Sham, 1.50g povidone K29/32, 5.00g mannitol, 1.00g silicon dioxide, 4.00g crospovidone, 29.94g microcrystalline cellulose, 0.50g magnesium stearate and 5g film coating pre Mixture (enteric-coated type), preferably, the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, most preferably 50-150nm.
  • the particle size of the ROCK2 inhibitor is 50-1000nm, preferably 50-500nm, more preferably 50-300nm, most preferably 50-150nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal preparation is a nanocrystal enteric-coated tablet, comprising 5.56g ROCK2 inhibitor, 1.50g polysorbate 80, 1.00g porol Sham, 1.50g povidone K29/32, 38.94g mannitol, 1.00g silicon dioxide, 0.50g magnesium stearate and 5g film coating premix (enteric coating type), preferably, the ROCK2 inhibitor
  • the particle size of the agent is 50-1000 nm, preferably 50-500 nm, more preferably 50-300 nm, most preferably 50-150 nm.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal preparation is a nanocrystal enteric-coated capsule, comprising:
  • ROCK2 inhibitor preferably 10-20% ROCK2 inhibitor, more preferably 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19% or 20% ROCK2 inhibitor; and
  • - 10-50% stabilizer preferably 20-40% stabilizer, more preferably 30-40% stabilizer, eg 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37% %, 38%, 39% or 40% stabilizer.
  • the present invention relates to a nanocrystal preparation, wherein the nanocrystal preparation is a nanocrystal enteric capsule, comprising 11.1g of ROCK2 inhibitor, 3.0g of polysorbate 80, 2.0g of poloxamer, 3.0g povidone K29/32, 20.0g mannitol, 2.00g silicon dioxide, 8.0g crospovidone, 29.9g microcrystalline cellulose, 1.0g magnesium stearate and enteric-coated capsules, preferably, all
  • the particle size of the ROCK2 inhibitor is 50-1000 nm, preferably 50-500 nm, more preferably 50-300 nm, most preferably 50-150 nm.
  • the ROCK2 inhibitor may comprise, in addition to the compound of formula (I), (II), (III) or formula (IV), or a pharmaceutically acceptable salt or hydrate thereof, Optionally at least one other compound that has a synergistic therapeutic effect with the compound is included.
  • the present invention relates to a method for preparing the above-mentioned nanocrystal preparation, which comprises grinding a ROCK2 inhibitor and a stabilizer.
  • the present invention relates to the preparation method of the above-mentioned nanocrystalline preparation, wherein the weight ratio of ROCK2 inhibitor and stabilizer during grinding is 1:15 to 15:1, 1:14 to 14:1, 1:13 to 13:1, 1:12 to 12:1, 1:11 to 11:1, 1:10 to 10:1, 1:9 to 9:1, 1:8 to 8:1, 1:7 to 7 :1, 1:6 to 6:1, 1:5 to 5:1, 1:4 to 4:1, 1:3 to 3:1, 1:2 to 2:1, 1:1; preferably,
  • the weight ratio of ROCK2 inhibitor to stabilizer when grinding is 15:1 to 2:1, more preferably 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, 10:3 , 9:1, 8:1, 7:1, 6:1, 5:1, 4:1, 3:1 or 2:1.
  • the present invention relates to the preparation method of the above-mentioned nanocrystalline preparation, wherein the grinding medium is selected from ceramic balls, glass balls, zirconia beads, steel balls or ice beads; preferably, the grinding medium is zirconia beads .
  • the present invention relates to a method for preparing the above-mentioned nanocrystalline preparation, wherein the particle size of the grinding medium is in the range of 0.1-1 mm, preferably 0.1-0.5 mm, more preferably 0.2 mm.
  • the present invention relates to the preparation method of the above-mentioned nanocrystal preparation, wherein the grinding time is 0.1-6h, preferably 0.5-6h, preferably 4-6h, more preferably 10min, 20min, 30min, 40min, 1h , 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h or 6h.
  • the present invention relates to the preparation method of the above-mentioned nanocrystalline preparation, wherein the grinding speed is 1000-6000rpm, preferably 1500rpm-4500rpm, more preferably 1500rpm, 2000rpm, 2500rpm, 3000rpm, 3500rpm, 4000rpm, 4500rpm, 5000rpm , 5500rpm or 6000rpm.
  • the present invention relates to the preparation method of the above-mentioned nanocrystal preparation, wherein the filling amount of grinding beads is 50-95%, preferably 70%-90%, more preferably 70%, 80% or 90%.
  • the present invention relates to the preparation method of the above-mentioned nanocrystal preparation, wherein, before grinding the ROCK2 inhibitor and the stabilizer, a pre-grinding step is further included.
  • the present invention relates to the preparation method of the above-mentioned nanocrystal preparation, wherein, the pre-grinding speed is 3000-6000rpm, preferably 3000rpm, 3500rpm, 4000rpm, 4500rpm, 5000rpm, 5500rpm or 6000rpm, more preferably 4000rpm;
  • the pre-grinding time is 1-30 min, preferably 2-20 min, preferably 3 min, 4 min, 5 min, 6 min, 8 min, 10 min, 12 min, 15 min, 18 min or 20 min, more preferably 5 min.
  • the present invention relates to a method for preparing the above-mentioned nanocrystalline preparation, wherein stabilizers and/or excipients are optionally added after grinding.
  • the present invention relates to the preparation method of the above-mentioned nanocrystalline preparation, wherein, the stabilizer added after grinding is selected from polysorbate, povidone, polyoxyethylene fatty acid ester, polyethylene glycol, polyvinyl alcohol , hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, poloxamer, sodium lauryl sulfate, docusate sodium, 15-hydroxystearic acid polyethylene glycol, polyoxyethylene One or more of castor oil, copovidone, lactose, mannitol.
  • the stabilizer added after grinding is selected from polysorbate, povidone, polyoxyethylene fatty acid ester, polyethylene glycol, polyvinyl alcohol , hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, poloxamer, sodium lauryl sulfate, docusate sodium, 15-hydroxystearic acid polyethylene glycol, polyoxyethylene
  • the present invention relates to the preparation method of the above-mentioned nanocrystalline preparation, wherein, the stabilizer added after grinding is selected from povidone K29/32, poloxamer 188, polyvinyl alcohol, lactose and mannitol one or more.
  • the present invention relates to the preparation method of the above-mentioned nanocrystalline preparation, wherein the stabilizer added after grinding is a mixture of povidone K29/32 and poloxamer 188, and the mixing ratio of the two is 1:10 to 10:1, preferably 1:9 to 9:1, preferably 1:8 to 8:1, preferably 1:7 to 7:1, preferably 1:6 to 6:1, preferably 1:5 to 5:1, preferably 1:4 to 4:1, preferably 1:3 to 3:1, preferably 1:2 to 2:1, preferably 1:1; more preferably, the mixing ratio of the two is 1:4, 4:1 or 1:1.
  • the stabilizer added after grinding is a mixture of povidone K29/32 and poloxamer 188
  • the mixing ratio of the two is 1:10 to 10:1, preferably 1:9 to 9:1, preferably 1:8 to 8:1, preferably 1:7 to 7:1, preferably 1:6 to 6:1, preferably 1:5 to 5:1, preferably 1:4 to 4:1, preferably 1:3 to 3:1
  • the present invention relates to the preparation method of above-mentioned nanocrystal preparation, it comprises:
  • the active ingredient, part of the stabilizer and purified water are ground with a nano-grinding machine to obtain a nano-suspension, and then adding a stabilizer and/or a filler to obtain a nano-crystal suspension.
  • a nano-grinding machine to obtain a nano-suspension
  • a stabilizer and/or a filler to obtain a nano-crystal suspension.
  • the nanosuspension is obtained by grinding, it is solidified by spray drying or freeze drying to obtain a solid nanocrystalline mixture, then adding fillers for mixing, adding a lubricant, and then molding.
  • the molding process may include granulation, optionally sizing, and tableting or capsule filling.
  • the key process in the present invention is the nano-grinding process.
  • the mixing and the subsequent molding process are all conventional processes and operations in the technical field, and the present invention is not specifically limited here.
  • the inventors investigated the effects of grinding speed, filling amount of grinding beads, sample amount and grinding time on the particle size of ROCK2 inhibitors.
  • the results show that the particle size of ROCK2 inhibitor decreases gradually with the increase of grinding time, but the decreasing speed gradually slows down; as the grinding speed increases, the grinding efficiency increases; at the same speed, the grinding bead filling increases, and the grinding efficiency also increases .
  • the sample size had no significant effect on the grinding efficiency.
  • the grinding parameters and particle size study results are shown in Table 8. Based on this, in some embodiments of the present invention, in the grinding process, 0.2mm zirconia grinding beads are used, and the filling amount of the grinding beads is 50%-95%, preferably 70%-90%.
  • the grinding speed is 1000 rpm to 4500 rpm, preferably 1500 rpm to 3500 rpm.
  • the grinding time is 2h-6h, preferably 4h-5h.
  • the ground nanosuspension when the nanocrystalline preparation composition contains a lubricant, the ground nanosuspension needs to be spray-dried or freeze-dried to remove moisture, and then directly or crushed with optional filler mix, then
  • the present invention relates to a method for preventing, alleviating and/or treating idiopathic pulmonary fibrosis, fatty liver disease and/or steatohepatitis, graft-versus-host disease or viral infection after hematopoietic stem cell transplantation, which It includes administering to the subject a therapeutically effective amount of the nanocrystal preparation or the nanocrystal preparation prepared by the method; preferably, the method is to prevent, alleviate and/or treat fatty liver disease and/or steatohepatitis method; preferably, the fatty liver disease is alcoholic fatty liver disease (ALFD) or nonalcoholic fatty liver disease (NALFD), and the steatohepatitis is alcoholic hepatitis (ASH) or nonalcoholic steatohepatitis (NASH), the hematopoietic stem cell transplantation is allogeneic hematopoietic stem cell transplantation, the graft-versus-host disease is acute graft-versus-host disease
  • the present invention relates to the use of the nanocrystal preparation or the nanocrystal preparation prepared by the method for preventing, alleviating and/or treating idiopathic pulmonary fibrosis, fatty liver disease and/or fatty liver disease Hepatitis, graft-versus-host disease or viral infection after hematopoietic stem cell transplantation; preferably, the nanocrystal preparation is used to prevent, relieve and/or treat fatty liver disease and/or steatohepatitis; preferably, the steatohepatitis
  • the liver disease is alcoholic fatty liver disease (ALFD) or nonalcoholic fatty liver disease (NALFD)
  • the steatohepatitis is alcoholic hepatitis (ASH) or nonalcoholic steatohepatitis (NASH)
  • the hematopoietic stem cell transplantation It is allogeneic hematopoietic stem cell transplantation, the graft-versus-host disease is acute graft-versus-host disease or chronic
  • the present invention relates to the preparation of the nanocrystal preparation or the nanocrystal preparation prepared by the method for preventing, alleviating and/or treating idiopathic pulmonary fibrosis, fatty liver disease and/or fatty Graft-versus-host disease or virus infection after hematopoietic stem cell transplantation; preferably, the use is to prepare a drug for preventing, alleviating and/or treating fatty liver disease and/or steatohepatitis purposes in; preferably, the fatty liver disease is alcoholic fatty liver disease (ALFD) or nonalcoholic fatty liver disease (NALFD), and the steatohepatitis is alcoholic hepatitis (ASH) or nonalcoholic fatty liver disease Hepatitis (NASH), the hematopoietic stem cell transplantation is allogeneic hematopoietic stem cell transplantation, the graft-versus-host disease is acute graft-versus-host disease or chronic graft-versus-host disease, and the virus infection is cor
  • the present invention will be further described below in conjunction with specific embodiments.
  • the specific conditions of the test methods are usually implemented according to the conventional conditions or the conditions suggested by the manufacturer; the raw materials and reagents are all obtained from the market or prepared using public information.
  • the active ingredient (API) used in the following comparative examples, examples and tests is the compound of formula (IV).
  • Preparation method Weigh the prescription amount of API hydrochloride, lactose, microcrystalline cellulose and croscarmellose sodium, mix, dry granulate, add magnesium stearate after granulation, mix, and compress into tablets.
  • Preparation method first micronize API hydrochloride to obtain API hydrochloride with a particle size of D 90 of about 2 ⁇ m, weigh the prescription amount of micronized API hydrochloride, lactose, microcrystalline cellulose and croscarmellose Sodium cellulose is mixed, dry granulated, after granulation, magnesium stearate is added, mixed, and tabletted.
  • Preparation method Weigh the prescription amount of API hydrochloride, silicon dioxide, pregelatinized starch 1500, microcrystalline cellulose, crospovidone and magnesium stearate half of the prescription, mix, dry granulate, and add after granulation The other half is mixed with crospovidone and magnesium stearate, and compressed into tablets.
  • Preparation method take recipe quantity API hydrochloride, polysorbate 80 and part of purified water, grind with nano grinder (0.2mm grinding beads, filling capacity 70%), grinding speed 1500rpm, time 10min, obtain average particle size 1868nm Add the solution of povidone K29/32 again, dilute to 250g, obtain final product concentration 40mg/mL (calculated as free base), product particle diameter 1875nm.
  • the grinding speed is 1500rpm, and the time is 20min to obtain a nanosuspension with an average particle diameter of 1006nm, then add the solution of povidone K29/32, and dilute to 250g to obtain a final product concentration of 40mg/mL (in the form of free Alkali meter), product particle size 1080nm.
  • the grinding speed is 1500rpm, and the time is 40min to obtain a nanosuspension with an average particle diameter of 512nm, then add the solution of povidone K29/32, and dilute to 250g to obtain a final product concentration of 40mg/mL (in the form of free Alkali meter), product particle size 540nm.
  • Preparation method Weigh the prescription amount of API hydrochloride, polysorbate 80 and part of purified water, grind with a nano grinder (0.2mm grinding beads, filling capacity 70%), grind at a speed of 1500rpm, and take 6h to obtain an average particle size of 268nm Add the solution of povidone K29/32, dilute to 250g, obtain final product concentration 40mg/mL (calculated as free base), product particle diameter 300nm.
  • Preparation method Weigh the prescription amount of API hydrochloride, polysorbate 80 and part of purified water, grind with a nano grinder (0.2mm grinding beads, filling capacity 70%), grind at a speed of 1500rpm, and take 6h to obtain an average particle size of 268nm Add the solution of povidone K29/32 again, dilute to 250g, obtain final product concentration 40mg/mL (calculated as free base), product particle diameter 302nm.
  • Preparation method Weigh the prescription amount of API hydrochloride, polysorbate 80 and part of purified water, grind with a nano grinder (0.2mm grinding beads, filling capacity 70%), grind at a speed of 1500rpm, and take 6h to obtain an average particle size of 268nm Add the solution of hypromellose to dilute to 250g to obtain the final product concentration of 40mg/mL (in terms of free base), and the product particle size is 336nm.
  • Preparation method Weigh the prescription amount of API hydrochloride, polysorbate 80 and part of purified water, grind with a nano grinder (0.2mm grinding beads, filling capacity 70%), grind at a speed of 1500rpm, and take 6h to obtain an average particle size of 268nm Add the solution of hypromellose to dilute to 250g to obtain the final product concentration of 40mg/mL (calculated as free base), and the product particle size is 442nm.
  • Preparation method take the prescription amount of API hydrochloride, polysorbate 80 and part of purified water, grind with a nano grinder (0.2mm grinding beads, filling capacity 70%), grind at a speed of 1500rpm, and take 4h to obtain an average particle size of 281nm
  • a nano grinder 0.2mm grinding beads, filling capacity 70%
  • grind at a speed of 1500rpm and take 4h to obtain an average particle size of 281nm
  • the particle size is 283nm.
  • Preparation method Weigh the prescription amount of API hydrochloride, polysorbate 80 and part of purified water, grind with a nano grinder (0.2mm grinding beads, filling capacity 90%), grind at a speed of 3000rpm, and take 4h to obtain an average particle size of 100nm Add the solution of methylparaben, propylparaben and polyoxyethylene castor oil prepared in advance, and dilute to 1240.62g to obtain a final product concentration of 40mg/mL (calculated as free base). The particle size is 106nm.
  • Preparation method Weigh the prescription amount of API hydrochloride, polysorbate 80 and part of purified water, grind with a nano grinder (0.2 mm grinding beads, filling capacity 90%), grind at a speed of 4500 rpm, and take 6 hours to obtain a nanocrystal suspension Liquid, particle size 58nm, then add polyethylene glycol 6000 and lactose solution prepared in advance, carry out spray-drying, air inlet temperature 120 °C, spray speed 40rpm, get spray-dried powder.
  • a nano grinder 0.2 mm grinding beads, filling capacity 90%
  • Preparation method Weigh the prescription amount of API hydrochloride, polysorbate 80 and part of purified water, grind with a nano grinder (0.2 mm grinding beads, filling capacity 90%), grind at a speed of 4500 rpm, and take 6 hours to obtain a nanocrystal suspension Liquid, particle size 58nm, then add polyethylene glycol 6000 and lactose solution prepared in advance, carry out spray-drying, air inlet temperature 120 °C, spray speed 40rpm, get spray-dried powder.
  • a nano grinder 0.2 mm grinding beads, filling capacity 90%
  • Preparation method Weigh the prescription amount of API hydrochloride, polysorbate 80 and part of purified water, grind with a nano grinder (0.2 mm grinding beads, filling capacity 90%), grind at a speed of 3000 rpm, and take 6 hours to obtain a nanocrystal suspension Liquid, particle size 89nm, then add polyethylene glycol 6000 and lactose solution prepared in advance, spray drying, air inlet temperature 120 °C, spray speed 40rpm, to obtain spray-dried powder.
  • a nano grinder 0.2 mm grinding beads, filling capacity 90%
  • Preparation method Weigh the prescription amount of API hydrochloride, polysorbate 80 and part of purified water, grind with a nano-grinding machine (0.2 mm grinding beads, filling capacity 90%), grind at a speed of 3000 rpm, and take 4 hours to obtain a nanocrystal suspension Liquid, particle size 128nm, then add polyethylene glycol 6000 and lactose solution prepared in advance, freeze-dry (solid content of sample solution is about 20%), pre-freeze at -40°C for 5h, main dry at -5°C for 13h, vacuum 0.18mbar, secondary drying at 10 ⁇ 15°C for 16h, vacuum degree 0.18mbar.
  • the sample was pulverized and granulated with a pulverizing and granulating machine, mixed with silicon dioxide, spray-dried mannitol and sodium stearyl fumarate (internal addition), dry granulated, mixed with externally added sodium stearyl fumarate, and pressed Tablets, weighing about 1g (specification 200mg, based on anhydrous API).
  • the sample was pulverized and granulated with a granulator, and then mixed with silicon dioxide, spray-dried mannitol and sodium stearyl fumarate, and pressed into tablets with a weight of about 1 g (specification 200 mg, based on anhydrous API).
  • Embodiment 26 enteric-coated nanochip tablet
  • Preparation method Weigh the prescription amount of API hydrochloride, polysorbate 80 and part of purified water, grind with a nano grinder (0.2 mm grinding beads, filling capacity 90%), grind at a speed of 3000 rpm, and take 6 hours to obtain a nanocrystal suspension solution, particle size 109nm, and then add pre-prepared poloxamer, povidone K29/32, and mannitol solution, freeze-dry (solid content of sample solution is about 20%), pre-freeze at -40°C for 5h, and main dry -5°C for 13h, vacuum degree 0.18mbar, secondary drying at 10-15°C for 16h, vacuum degree 0.18mbar.
  • the sample is pulverized and granulated with a pulverizing and granulating machine, mixed with silicon dioxide, microcrystalline cellulose, crospovidone and magnesium stearate, and compressed into tablets.
  • the weight of the tablet is about 1g (specification 100mg, according to water API meter).
  • Use the film coating premix (enteric-coated type) for enteric coating prepare a coating material with a solid content of 20%, and coat under stirring.
  • the inlet air temperature is 45°C
  • the air volume is 200m3/min
  • the tablet bed temperature is 31°C.
  • the rotating speed of the coating pan is 15-18 rpm
  • the spraying speed of the coating solution is 5g/min
  • the weight gain of the coating is 9.9%.
  • Embodiment 27 enteric-coated nanochip tablet
  • Preparation method Weigh the prescription amount of API hydrochloride, polysorbate 80 and part of purified water, grind with a nano grinder (0.2 mm grinding beads, filling capacity 90%), grind at a speed of 3000 rpm, and take 6 hours to obtain a nanocrystal suspension solution, particle size 109nm, then add pre-prepared poloxamer, povidone K29/32, and mannitol solution (mannitol accounts for 15%), and freeze-dry (the solid content of the sample solution is about 20%). Freezing at -40°C for 5h, main drying at -5°C for 13h, vacuum at 0.18mbar, secondary drying at 10-15°C for 16h, vacuum at 0.18mbar.
  • the sample was pulverized and granulated with a granulator, and mixed with silicon dioxide, mannitol (33.94g) and magnesium stearate, and pressed into tablets. .
  • film coating premix enteric-coated type
  • enteric coating prepare a coating material with a solid content of 20%, and coat under stirring.
  • the inlet air temperature is 48°C
  • the air volume is 200m3/min
  • the tablet bed temperature is 36°C.
  • the rotating speed of the coating pan is 15-20 rpm
  • the spraying speed of the coating solution is 5g/min
  • the coating weight gain is 10.0%.
  • Preparation method Weigh the prescription amount of API hydrochloride, polysorbate 80 and part of purified water, grind with a nano grinder (0.2 mm grinding beads, filling capacity 90%), grind at a speed of 3000 rpm, and take 6 hours to obtain a nanocrystal suspension solution, particle size 109nm, then add pre-prepared poloxamer, povidone K29/32, and mannitol solution (mannitol accounts for 15%), and freeze-dry (the solid content of the sample solution is about 20%). Freezing at -40°C for 5h, main drying at -5°C for 13h, vacuum at 0.18mbar, secondary drying at 10-15°C for 16h, vacuum at 0.18mbar.
  • the sample was pulverized and granulated with a pulverizer and granulator, and silicon dioxide, microcrystalline cellulose, mannitol (15g), crospovidone and magnesium stearate (0.25g) were added, mixed, and dry granulated , passed through a 24-mesh sieve for granulation, added magnesium stearate (0.25g) and mixed, manually filled enteric-coated capsules, size 00, with a filling amount of 800mg (specification 100mg, calculated according to anhydrous API).
  • Dissolution medium purified water, 0.3SDS aqueous solution, 0.5% SDS aqueous solution, 0.8% SDS aqueous solution, 1.0% SDS aqueous solution, pH2.0 hydrochloric acid solution+1.0%SDS, pH4.5 acetate solution+1.0%SDS, pH6 .8 phosphate solution + 1.0% SDS, 3% Tween solution; 900ml;
  • Reference substance solution preparation Take about 25mg of the reference substance, weigh it accurately, place it in a 100mL volumetric flask, add about 2mL DMSO, dissolve it by ultrasonication, then dilute to the mark with the diluent of the corresponding medium, and shake well.
  • the API ordinary sheet prepared by Comparative Example 3 of the present invention is insoluble in pure water, and is insoluble in water containing different concentrations of sodium dodecyl sulfate (SDS) and at different pHs.
  • SDS sodium dodecyl sulfate
  • the dissolution rate of the tablets prepared by micronizing the API was not significantly improved.
  • Adding an appropriate amount of silicon dioxide and optimizing the formulation showed a greater improvement in the product dissolution rate, but at SDS concentration ⁇ 0.5 % dissolution rate in the medium is still low.
  • the dissolution rate of the nanocrystalline suspension preparation prepared by the embodiments of the present invention 8-9 is significantly higher than that of the common tablet, and it is 15min in the low SDS concentration (3%) medium. The dissolution rate reaches more than 85%. But when the SDS concentration was further reduced to 2%, the sample precipitated out in the late stage of dissolution. Using 3% Tween medium instead, the dissolution rates of the two nanocrystal suspensions in Example 8 and Example 9 were significantly improved, and the samples were stable without precipitation.
  • the dissolution rate of the nano-chip preparations prepared by Examples 10-15 of the present invention is significantly improved compared with the dissolution rate of ordinary tablets. Slower, 2h dissolution rate is similar.
  • the dissolution rate of the nanocrystalline capsule prepared by the embodiment of the present invention 24-25 is significantly improved compared with the dissolution rate of the common tablet, and compared with the nano-chip tablet, the dissolution is accelerated in 1h and before, and the dissolution rate is faster after 1h.
  • the post-dissolution rates were similar. Compared with the nanocrystal suspension, the dissolution rate is slower at 15 minutes and before, and the dissolution rate is similar after 15 minutes.
  • the product specification was changed from 200mg to 100mg, and the corresponding dissolution medium volume was changed from 900ml to 500ml.
  • the average particle diameter result of the suspension before and after drying the nanocrystalline powder that adds different stabilizers after table 7 grinding
  • the inventors investigated the influence of grinding speed, filling amount of grinding beads, sample amount and grinding time on the particle size of API.

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Abstract

L'invention concerne une préparation nanocristalline et son procédé de préparation, la préparation nanocristalline comprenant un inhibiteur de ROCK2 et un stabilisant. La présente invention concerne également l'utilisation de la préparation nanocristalline dans la prévention, le soulagement et/ou le traitement de maladies et d'affections médicales sélectionnées, en particulier de maladies telles que la fibrose pulmonaire idiopathique, la stéatose hépatique et/ou la stéatohépatite, la maladie du greffon contre l'hôte post-greffe de cellules souches hématopoïétiques ou une infection virale.
PCT/CN2022/131872 2021-11-16 2022-11-15 Préparation nanocristalline d'inhibiteur de rock2 et son procédé de préparation WO2023088231A1 (fr)

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Citations (5)

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Publication number Priority date Publication date Assignee Title
WO2019001572A1 (fr) * 2017-06-30 2019-01-03 北京泰德制药股份有限公司 Inhibiteur de protéine kinase associée à rho, composition pharmaceutique le comprenant, son procédé de préparation et son utilisation
WO2019000683A1 (fr) * 2017-06-30 2019-01-03 北京泰德制药股份有限公司 Inhibiteur de protéine kinase associée à rho, composition pharmaceutique contenant celui-ci, son procédé de préparation et ses applications
WO2019000682A1 (fr) * 2017-06-30 2019-01-03 北京泰德制药股份有限公司 Inhibiteur de protéine kinase associée à rho, composition pharmaceutique contenant celui-ci, son procédé de préparation et ses applications
WO2020177587A1 (fr) * 2019-03-01 2020-09-10 北京泰德制药股份有限公司 Méthode de traitement d'une stéatose hépatique et/ou d'une stéatohépatite
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WO2020177587A1 (fr) * 2019-03-01 2020-09-10 北京泰德制药股份有限公司 Méthode de traitement d'une stéatose hépatique et/ou d'une stéatohépatite
WO2020259528A1 (fr) * 2019-06-25 2020-12-30 北京泰德制药股份有限公司 Procédé de traitement de la fibrose pulmonaire idiopathique

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